<%-- Document : heatshock Created on : Dec 8, 2009, 1:50:12 PM Author : amberbm --%> <%@page contentType="text/html" pageEncoding="UTF-8"%> Ransplantation Reviews
Immunob
iology

Heat Shock Proteins in Transplant Immunity*

by

René J. Duquesnoy, Ph.D.

Professor of Pathology and Surgery,

University of Pittsburgh Medical Center.

*This is an abbreviated and updated version of an article published in Transplantation Reviews 10:175-187, 1996.

Introduction

Cellular rejection of transplanted organs is mediated by donor-specific T lymphocytes which via direct and indirect allorecognition of Major Histocompatibility Complex (MHC) antigens, exert cytotoxic effects on donor tissues and through lymphokine release, recruit and activate inflammatory cells that cause graft injury. Nevertheless, rather low frequencies of donor MHC-specific T cells (in the order of less than one percent to a few percent) are detected in rejecting allografts. In other words, the majority of graft-infiltrating lymphocytes do not function through MHC allorecognition and must react through other specificity mechanisms. Such lymphocytes may recognize minor histocompatibility antigens and the so-called tissue-specific antigens, but they can likely not account for a large proportion of graft-infiltrating cells. Therefore, other mechanisms of lymphocyte activation must be involved in intragraft transplant immunity.

We have forwarded the concept that during rejection, the allograft undergoes a stress response which leads to increased expression of heat shock proteins (hsp) and triggers the infiltration and activation of hsp-responsive lymphocytes. This immune triggering by the stress response might be similar the danger signal concept proposed by Matzinger.

This review addresses the role of heat shock proteins in transplant immunity in particular acute chronic rejection. Topics include the expression of hsp in transplanted tissues and the role of hsp in humoral and cellular aspects of transplant immunity. Some background information is provided about hsp and their relevance in the immunology of certain disease conditions.

What are heat shock proteins?

Also called stress proteins, hsp are common constituents of all types of prokaryotic and eukaryotic cells and they exhibit a high level of evolutionary conservation. Originally identified in cells exposed to sudden elevations in temperature, hsp mediate responses to a variety of stressful stimuli including ischemia and inflammation. They play a major role in various cellular compartments by functioning as molecular chaperones involved in the assembly, folding and translocation of intracellular polypeptides, to interact with various receptors and in stressed cells, to restore the functional activity of denatured proteins. Increased intracellular hsp levels increase the cellular resistance to injury. Many stress proteins have been classified as hsp according to molecular weight in kilodaltons. For instance, hsp60 operates primarily in mitochondria whereas the cytosolic compartment contains the stress-inducible hsp72 and the constitutively expressed hsp73 (also called hsc73). Other stress proteins are referred to as glucose-regulated proteins (grp) because they were originally discovered in culture systems deprived of glucose. Grp78 (also called BiP) and grp94 are molecular chaperones that operate primarily in the endoplasmic reticulum whereas grp75 is found primarily in mitochondria. Many stress proteins, especially the members of the hsp70 family, have a common structure consisting of an amino-terminal domain with ATPase activity and an carboxy-terminal domain with structural similarities to the peptide-binding region of MHC molecules. Several stress proteins participate in the biogenesis of class I and class II molecules and in antigen processing and presentation.

The spectrum of stress proteins is extremely diverse and includes many other hsp including hsp27, hsp32 (also called hemoxygenase-1), hsp40 and hsp47 (or colligin) and nitric oxide synthetase, protein disulfide isomerase and many others. This review deals primarily with members of the hsp60 and hsp70 families.

Heat shock proteins in autoimmune disease and in tumor immunity

The medical importance of stress proteins is apparent from numerous studies on infection, inflammation, autoimmune disease and tumor immunity (for a comprehensive review see: W. van Eden and D.B. Young (Editors). Stress Proteins in Medicine. New York: Marcel Dekker. Inc., 1996). During infection, humoral and cellular immune responses are often directed to microbial hsp. Injurious stimuli to tissues induce an increased production of hsp that may activate the immune system. In many experimental models and clinical situations, hsp-responsive lymphocytes have been shown to participate in the pathogenesis of several autoimmune diseases. Hsp60-reactive T cells are present in synovial fluids from arthritis patients and hsp70-reactive T-cells appear in spinal fluids and demyelinated lesions of multiple sclerosis patients. Peripheral T cell reactivity against hsp60 and increased serum levels of hsp60-specific antibodies have been reported for diabetes, atherosclerosis and many other diseases.

Hsp have also been implicated in the pathogenesis of experimentally induced autoimmune disease. For example, van Eden's group has shown that T cells specific for the 180-188 sequence of mycobacterial hsp65 confer adjuvant arthritis in rats and that vaccination with the 256-270 peptide provides protection. In a murine model of insulin-dependent diabetes, Cohen's group has identified T cells that are specific for an epitope corresponding to an amino acid sequence shared between mycobacterial and mammalian hsp60. Administration of this peptide prevented diabetes in this model.

Stress proteins are also involved in tumor immunity. Srivastava has shown that grp94 (or gp96), hsp70 and hsp90 isolated from methylcholanthrene-induced murine sarcomas elicit immune responses causing a specific regression of transplanted tumors These hsp are associated with antigenic peptides that are chaperoned within and outside the endoplasmic reticulum during antigen processing and presentation by MHC molecules. Other groups have also demonstrated a role for hsp70 in anti-tumor resistance. Eberlein's group postulated that tumor tissue may undergo a stress response and that a portion of tumor-infiltrating lymphocytes may recognize stress proteins. Tumor-derived CD4 T cell lines can react with heat-stressed B cell lines through hsp70 recognition. Hsp60-specific T cells have been identified with antitumor activity against a murine sarcoma and that injection of mice with tumor cells transfected with mycobacterial hsp65 induces immune protection against the original tumor. Another mechanism of immune lysis of tumor cells seems related to the surface expression of hsp70.

In conclusion, several concepts have emerged to explain the mechanism(s) how stress proteins play a role in tumor immunity and the pathogenesis of autoimmune disease. It seems likely that similar concepts may evolve regarding the participation of stress proteins in transplant immunity,

Expression of stress proteins in transplanted tissues

The first paper on stress proteins in transplantation was published in 1987 by Currie who reported an increased expression of hsp72 in rejecting rat cardiac allografts. Perdrizet observed that prior treatment of donor rats with heat shock and a 6-8 hour recovery period enhances the expression of hsp72 and the prolongs transplant survivals of donor kidneys.

With a rat model of heterotopic heart transplant rejection, Qian et al. distinguished three types of stressful stimuli that increase the hsp expression in the allograft, namely ischemia/ reperfusion injury, the appearance of graft-infiltrating lymphoid cells and finally, the inflammatory stage of the rejection process (Table 1). During the first few days following transplantation, both allografts and syngrafts exhibit increased expression of hsp60, hsp72, grp75 and grp78. Allografts show further increases in grp78 and grp94 expression on day 3 post-transplant when alloreactive lymphocytes begin to infiltrate the allograft. During the inflammatory stage of rejection, there are several lower molecular weight bands which might represent degradation products of hsp60, hsp72 and grp78.

Table 1. Three Stages of Stress Protein Expression in Stromal Tissues of Rat Heart Allografts

 

Ischemia/Reperfusion Injury

Day 1-2

Appearance of Cellular Infiltrate

Day 2-3

Rejection-Associated Inflammation

Day 4-5

Hsp60

+

+

+ D

Hsp72

+

+

+/- D

Hsc73

o

+/-

+/- D

Grp75

+

+

+/-

Grp78

+

++

+ D

Grp94

+

+

o

Comparisons were made in Western blots with syngrafts and normal hearts and the levels were expressed as o : no increase, +/- : modest or variable increase, + : definite increase and ++ : marked increase. D indicates the presence of crossreacting lower molecular weight bands presumably representing degraded forms of hsp molecules.

Davies et al. and Baba et al. have also reported the increased expression of hsp70 in allografts undergoing rejection. The article in Transplant Revs and recent immunohistochemical data provide further documentation that the stress response of an allograft during the various stages of rejection involves a wide spectrum of heat shock proteins. An important aspect is that increased hsp expression may convey a cytoprotective effect from inflammatory injury. For instance, hsp70 protects cells from injury caused by reactive oxygen species including nitric oxide, and cytokines such as TNF-a. Other consequences of the increased hsp expression in the allograft involve immune activation. Most information generated so far with various transplant models deal with immune responses involving the hsp60 and hsp70 families

Humoral immunity to stress proteins.

The literature contains many reports describing the appearance of hsp-specific antibodies associated with various infections and autoimmune diseases. These antibodies react commonly with hsp60 but there are also many examples of humoral immunity to hsp70 and other heat shock proteins. Only a few transplantation-related studies have been published. Rose and co-workers have reported that the presence of high-titer antibodies to hsp60 and hsp70 correlates with a higher rejection rate in heart transplant patients. Clancy's group has observed elevated serum levels of antibodies reactive with hsp70 during the development of acute graft-versus-host disease in an F1 hybrid rat model.

Hsp-induced propagation of lymphocytes from human transplant tissues.

Our initial studies on stress proteins and cellular rejection were done with endomyocardial biopsies from heart transplant patients. These studies were based on the experience that the in vitro culturing of biopsied transplant tissues with Interleukin-2 (IL-2) permits the outgrowth of graft-infiltrating lymphocytes and that the frequency of biopsy growth correlates with the degree of cellular rejection. Moliterno et al. observed that the induction of lymphocyte growth with soluble Mycobacterium tuberculosis extract (a source of hsp) or recombinant mycobacterial hsp65 correlates with the histological rejection grade. These data provided first evidence that hsp-reactive T lymphocytes infiltrate transplanted hearts during rejection and we also noted significant proportions of TCRgd T lymphocytes (all of them had g9-negative, d1-positive phenotype) for long-term transplant survivors. Similar findings have been obtained by Trieb who propagated human T-cell lines from rejected kidney allografts. These cells proliferated to recombinant human hsp72 in combination with autologous (but not with allogeneic) peripheral blood mononuclear cells as antigen-presenting cells (APC).

TCR gd cells have been reported to react with hsp65 from mycobacteria and stressed mammalian tissue and such cells may participate in autoimmune reactions. Relevant are the findings by Wick's group on the upregulated hsp65 expression and the presence of hsp65-reactive TCR gd cells in arteriosclerotic lesions in an experimentally induced rabbit model (80). Several years ago, we reported the propagation of TCRgd cells from coronary arteries from long-term heart transplant patients with chronic rejection. No studies have been done to determine whether these TCRgd cells react with hsp generated during the stress response associated with chronic rejection.

Hsp-Reactivity of Lymphocytes Isolated from Heterotopic Rat Cardiac Allografts during Acute Rejection.

The rat heart transplant model has permitted more detailed studies of the effect of hsp on graft-infiltrating lymphocytes. Moliterno reported that incubation with mycobacterial hsp65 and especially hsp70 causes a marked increase of the proliferative response of allograft-derived cells to irradiated donor spleen cells as allogeneic APC. Very little proliferation takes place with hsp70 and syngeneic APC unless a small amount of IL-2 has been added to the culture. These findings suggest that IL-2 must be important for the hsp reactivity of intragraft lymphocytes. This hsp reactivity of allograft-infiltrating cells is first seen about three days post-transplant at the same time when alloreactive T cells appear (Figure 1). In contrast, lymphocytes isolated from syngrafts or allografts from tacrolimus-treated recipients exhibit no or very little proliferation in the presence of hsp and self-APC.

Figure 1. Proliferative responses of graft-infiltrating lymphocytes isolated from cardiac allografts during the first five days after transplantation. The assays were done with irradiated donor spleen cells (ACI-APC) or with irradiated syngeneic spleen cells (LEW-APC) and recombinant Mycobacterum tuberculosis hsp71 (Mtub71) with a small quantity of IL-2 (0.4U/ml).

Hsp71 dependency of autoreactive T cell clones cultured from allograft-infiltrating cells.

Allograft-derived lymphocyte clones are readily established by culturing with self-APC and recombinant Mycobacterium tuberculosis hsp71 (Mtub71) in the presence of IL-2. Liu, Moliterno et al. identified two groups of self-APC reactive T-cell clones, both of them are CD3+,CD4+,CD8- (Table 2). One group requires Mtub71 for self-APC-induced proliferation and IL-2 release and they are referred to as hsp71-dependent autoreactive T cells. These clones proliferate in the presence of soluble hsp71 and self-APC, but allogeneic or third-party APC are ineffective. Mtub71 does not appear to function as a conventional antigen because exposure to trypsin, ATP or polymyxin B abrogates its stimulatory activity. Rather, the Mtub71 effect appears mediated by structurally intact hsp70 molecules which will induce self-APC to become stimulatory to this group of autoreactive T cells.

Table 2. Proliferative responsiveness of three types of T cell clones cultured from rejecting rat heart allografts

 

Hsp71-dependent, autoreactive clones

Hsp71-independent, autoreactive clones

Donor-specific alloreactive clones

self-APC

no

yes

no

self-APC + Mycobacterial hsp71

yes

yes or more

no

allo-APC

no

no

yes

allo-APC + Mycobacterial hsp71

no

no

yes

The second group of autoreactive T cell clones respond readily to self-APC in the absence of Mtub71. These clones are referred to as hsp71-independent autoreactive lymphocytes, although their proliferative responses to self-APC are frequently augmented by Mtub71. Since this augmenting effect of Mtub71 is largely unaffected by trypsin, ATP or polymyxin B, it seems likely that its mechanism is different from the mechanism of hsp71-dependent autoreactive T cell stimulation by self-APC. This difference might reflect the stimulation of hsp71-independent autoreactive clones by self-APC through a self-restricted presentation of antigens in the Mtub71 preparation.

At present, we have not seen a significant Mtub71 effect on alloreactive T cell clones even after culturing with donor APC plus Mtub71. Therefore, hsp71-dependent and hsp71-independent, autoreactive T cells may represent distinct components of cellular rejection mediated by alloreactive T cells. Although their functional significance in transplant immunity remains to be established, we believe that hsp71-dependent, autoreactive T cells reflect a cellular immune mechanism associated with a stress response to the rejection process and tissue inflammation.

Effect of murine grp78 on hsp71-dependent T cells.

The autoreactive T-cell dependency not limited to mycobacterial hsp71, because incubation with mammalian (i.e. murine) grp78, a stress protein generally found in the endoplasmic reticulum, will also lead to proliferation of hsp71-dependent T-cell clones. This T-cell reactivity with grp78 becomes even more interesting because rejecting allografts have higher grp78 levels. Grp78 is constitutively expressed in mammalian cells and can be upregulated and even released under certain stress conditions.

Hsp immunity in a rat allograft model of chronic rejection

The stress response to injury concept may also be involved in the pathogenesis of chronic rejection. This hypothesis has been tested with a rat cardiac allograft model in recipients pretreated with donor bone marrow cells. Chronic rejection is manifested in this BM group by obliterative arteriopathy and the epicardium and endocardium contains lymphocytic infiltrates resembling Quilty lesions. Pre-treatment with a liver allograft (the OLTx group) is associated with an absence of chronic rejection in the transplanted heart.

Stress responses in 100-day allografts were assessed by determining heat shock protein (hsp) expression by immunohistology of graft tissues and Western blot analysis of stromal tissue lysates with monoclonal antibodies (mAb) to mammalian hsp60, the inducible hsp72, the constitutively expressed hsc73 and the C-terminal peptide sequence KSEKDEL of grp78 (grp78seq). All mAbs were obtained from StressGen Biotechnologies Corp (Victoria, B.C., Canada). Details of the immunostaining data are shown on our Web page: "Stress Protein Expression in a Rat Cardiac Allograft Model of Chronic rejection" Briefly, clusters of grp78seq-positive cells are seen in the inflammatory infiltrates of obliterated blood vessels and Quilty lesions in the BM group of cardiac allografts. Such grp78seq-positive cells were not seen in the OLTx group of heart allografts nor in syngrafts. Neither group showed significantly different graft myocyte staining of grp78 or hsp72 whereas hsp60 and hsc73 showed higher expression in the BM group and to a lesser extent the OLTx group. Western blot analysis of graft stromal tissue lysates showed additional bands with mAb to hsp60 and hsc73 for the OLTx and especially the BM group.

Lymphocytes isolated from chronically rejecting allografts reacted with irradiated autologous spleen cells in the presence of mycobacterial hsp65 and IL-2. Culturing of graft-infiltrating cells with mycobacterial hsp71 and IL-2 yielded lymphocyte lines without alloreactivity, but with strong proliferative responsiveness to self-APC, but only in the presence of mycobacterial hsp71 or murine grp78. This T-cell reactivity seemed to require intact hsp molecules because treatment of hsp71 with proteolyic enzymes, polymyxin or ATP abrogated this induction of the stimulatory effect of self-APC.

These findings support the concept that the pathogenesis of chronic rejection involves a stress response and the participation of graft-infiltrating autoreactive T-cells that operate under hsp-dependent mechanisms.

Mechanisms

Current experimental evidence supports the concept that during cellular rejection, graft-infiltrating cells induce a stress response within the allograft which increases the expression of heat-shock proteins and triggers the recruitment and activation of hsp-dependent lymphocytes. Whereas a variety of stress proteins exhibit higher tissue levels during the different phases of allograft rejection, our lymphocyte studies have dealt so far, primarily with the hsp70 family, namely mycobacterial hsp71 and murine grp78.

Hsp70 does not appear to stimulate graft-infiltrating T-cells as a conventional antigen. Rather, structurally intact hsp70 molecules seem to interact with self-APC, which then stimulate certain types of autoreactive CD4+ T-cells to undergo proliferation. This hsp effect implies a previously unrecognized mechanism of transplant immunity and the peptide-binding properties of stress proteins might be relevant. The members of the hsp70 family function as molecular chaperones which have a common structure consisting of a C-terminal peptide-binding domain and a N-terminal ATPase domain which influences peptide binding. For instance, grp78 can bind peptides of minimally 7-8 residues and the peptide-binding region contains four major pockets that can accommodate large hydrophobic residues. Through its peptide-binding properties, grp78 might participate in the transport and processing of autologous peptides presented by APC. Recent studies in Rammensee's laboratory have demonstrated that stress proteins such as grp94 (also called gp96) and PDI, participate through their peptide-binding properties, in alternative pathways of antigen processing and presentation. Grp94 and PDI are similar to grp78 in that they are resident proteins in the endoplasmic reticulum and that they are upregulated during a stress response. Tissue injury leads to a denaturation of intracellular proteins and an accumulation of protein degradation products. The stress response to tissue injury is manifested by elevated levels of heat shock proteins that function as chaperones in protein renaturation and in other cytoprotective processes. Conversely, the degradation of denatured proteins may generate (auto)antigenic peptides that bind to heat shock proteins such as grp78, grp94 and PDI and such complexes might be translocated into cellular compartments involved with antigen processing and presentation. Thus, stress responses may activate hsp-dependent pathways of (auto)antigen-induced T-cell activation..

Many papers have reported that APC stressed by heat, chemical treatment or ultraviolet irradiation, lose their ability to stimulate in mixed leukocyte cultures and Baird has shown that animals injected with stressed allogeneic cells often exhibit prolonged graft survivals and even transplant tolerance. Since stressed cells have increased hsp expression, it is possible that these effects might be related to hsp mediated immunomodulation.

Recent data of Krensky's group illustrate the involvement of hsp in the immunosuppression induced by certain HLA class I peptides. These peptides inhibit T cell function and promote rat allograft survival and this correlates with their binding to the constitutively expressed hsc70 and the heat-inducible hsp70. Noninhibitory peptides do not bind these hsp. Nadler et al have reported that the immunosuppressive effects of deoxyspergualin also involves the binding to hsc70 and this drug interferes with antigen presentation. Therefore, certain members of the hsp70 family have been proposed to represent a third class of immunophilins in addition to the cyclophilins and FK-binding proteins.

Conclusions

This review summarizes evidence that stress proteins are important in transplant immunity. Their major role seems related to antigen presentation. The stress protein concept in transplant immunity offers new perspectives of the various immune mechanisms leading to rejection, chronic dysfunction and conversely, transplant tolerance and how these processes are affected by infection and ischemia/reperfusion injury.

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